National Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China.
Int J Pharm. 2013 Sep 10;453(2):533-40. doi: 10.1016/j.ijpharm.2013.06.022. Epub 2013 Jun 21.
Growth hormone antagonist (GHA), an analog of growth hormone (GH), can inhibit GH action and treat acromegaly. However, GHA suffers from a short plasma half-life of 15-20 min that has limited its clinical application. PEGylation, conjugation with polyethylene glycol (PEG), can increase the plasma half-life of GHA. Single PEG attachment (mono-PEGylation) at N-terminus of GHA has the advantages of product homogeneity and minimization of the bioactivity loss. Conjugation of large PEG molecule may increase the plasma half-life but could potentially decrease the bioactivity of GHA, due to the steric shielding effect of PEG. Thus, N-terminal mono-PEGylation of GHA with 20 kDa and 40 kDa PEG were used to look for a balance of the two competing factors. Sedimentation velocity analysis suggested that 40 kDa PEG was more efficient than 20 kDa PEG to elongate the molecular shape of the conjugate. As reflected by marginal suppression of insulin-like growth factor I (IGF-I), GHA conjugated with 40 kDa PEG was statistically indistinguishable from the saline solution that could not inhibit GH action. In contrast, GHA conjugated with 20kDa PEG can apparently inhibit GH action, as reflected by IGF-I suppression of 30-43%. Thus, our work demonstrated the effective therapeutic potency of N-terminally mono-PEGylated GHA.
生长激素拮抗剂（GHA）是生长激素（GH）的类似物，可抑制 GH 的作用并治疗肢端肥大症。然而，GHA 的血浆半衰期较短，仅为 15-20 分钟，这限制了其临床应用。聚乙二醇化（PEGylation），即与聚乙二醇（PEG）的结合，可以延长 GHA 的血浆半衰期。GHA 的 N 端单 PEG 化（mono-PEGylation）具有产品均一性和最小化生物活性损失的优点。大 PEG 分子的结合可能会增加血浆半衰期，但由于 PEG 的空间位阻效应，可能会降低 GHA 的生物活性。因此，使用 20 kDa 和 40 kDa PEG 对 GHA 的 N 端进行单 PEG 化，以寻找这两个竞争因素之间的平衡。沉降速度分析表明，40 kDa PEG 比 20 kDa PEG 更有效地延长了缀合物的分子形状。如胰岛素样生长因子 I（IGF-I）的边际抑制所反映的那样，与生理盐水相比，与 40 kDa PEG 缀合的 GHA 在统计学上无明显差异，生理盐水不能抑制 GH 的作用。相比之下，与 20 kDa PEG 缀合的 GHA 可以明显抑制 GH 的作用，如 IGF-I 抑制 30-43%所反映的那样。因此，我们的工作证明了 N 端单 PEG 化 GHA 的有效治疗效力。
